Atomoxetine HCl is a selective norepinephrine reuptake inhibitor. It is marketed under the name STRATTERA® for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) and is available in 10 mg, 18 mg, 25 mg, 40 mg, and 60 mg dosage forms.
Atomoxetine, chemically known as (R)(−)—N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine, has the following structure:

Atomoxetine, the (R)-(−) enantiomer of tomoxetine, is an aryloxyphenylpropylamine. It is about twice as effective as the racemic mixture and about nine times more effective than the (+)-enantiomer, as disclosed in U.S. Pat. No. 4,018,895 (assigned to Eli Lilly and Co.), EP 0 052 492 (Eli Lilly and Co.), and EP 0 721 777 (Eli Lilly and Co.).
Optical resolution of racemic tomoxetine into (R)-(−)-tomoxetine (atomoxetine) and (S)-(+)-tomoxetine is known in the art both by chiral chromatography and fractional crystallization of (S)-(+)-mandelic acid diastereoisomeric addition salts.
The EP '492 patent describes a resolution process wherein racemic tomoxetine, prepared from N-methyl-3-hydroxy-3-phenylpropylamine, is resolved with (S)-(+)-mandelic acid to obtain (R)-(−)-tomoxetine (S)-(+)-mandelate salt in a poor yield of about 18%. This process is rather tedious and burdened by environmentally unfriendly solvents like diethyl ether and dichloromethane. Moreover, although it is known in the art that theoretical upper limit for yield in such optical resolution is 50%, the declared yield is rather low.
Subsequently, atomoxetine HCl may be prepared from (R)-(−)-tomoxetine (S)-(+)-mandelate by processes such as the one disclosed in EP Patent No. 0 052 492. In this process, (R)-(−)-tomoxetine (S)-(+)-mandelate is first basified in water to eliminate the mandelate, then extracted in diethyl ether. HCl gas is bubbled into the solution to obtain (R)-(−)-tomoxetine (atomoxetime) hydrochloride.
During the processes described above, a large amount of the racemic tomoxetine is lost in mother liquors as (S)-(+)-tomoxetine, the unwanted enantiomer. This is not advantageous from a commercial point of view, and the desired enantiomer is contaminated with the undesired (S)-(+)-tomoxetine enantiomer. In order to get the desired isomer, the final product requires purification by tedious and cumbersome purification processes such as column chromatography, HPLC or other techniques, thus making the approach commercially difficult to implement.
Enantiomeric purity studies performed on the commercial tablet, STRATTERA® 60 mg, showed that it contains the (S)-(+)-tomoxetine enantiomer at a level of 0.28% area by HPLC.
Stereochemical purity is of importance in the field of pharmaceuticals, where many of the most prescribed drugs exhibit chirality, and the two isomers exhibit different potency. Furthermore, optical purity is important since certain isomers may actually be deleterious rather than simply inert. Therefore, there's a need to obtain the desired enantiomer of atomoxetine HCl in high enantiomeric purity.
Additionally, in order to achieve a high efficiency of reaction for industrial scale synthesis of atomoxetine HCl, it is necessary to minimize the enantiomeric impurities, and obtain the desired isomer in high yields and a high optical purity.